Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex.

Publication Type:

Journal Article

Authors:

Himanen, Juha P; Goldgur, Yehuda; Miao, Hui; Myshkin, Eugene; Guo, Hong; Buck, Matthias; Nguyen, My; Rajashankar, Kanagalaghatta R; Wang, Bingcheng; Nikolov, Dimitar B

Source:

EMBO Rep, Volume 10, Issue 7, p.722-8 (2009)

Keywords:

Amino Acid Sequence, Cell Line, Crystallography, X-Ray, Drug Design, Ephrin-A1, Ephrin-A2, Humans, Ligands, Models, Molecular, Molecular Sequence Data, Protein Multimerization, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Eph Family, Sequence Alignment, Static Electricity

Abstract:

<p>Ephrin (Eph) receptor tyrosine kinases fall into two subclasses (A and B) according to preferences for their ephrin ligands. All published structural studies of Eph receptor/ephrin complexes involve B-class receptors. Here, we present the crystal structures of an A-class complex between EphA2 and ephrin-A1 and of unbound EphA2. Although these structures are similar overall to their B-class counterparts, they reveal important differences that define subclass specificity. The structures suggest that the A-class Eph receptor/ephrin interactions involve smaller rearrangements in the interacting partners, better described by a 'lock-and-key'-type binding mechanism, in contrast to the 'induced fit' mechanism defining the B-class molecules. This model is supported by structure-based mutagenesis and by differential requirements for ligand oligomerization by the two subclasses in cell-based Eph receptor activation assays. Finally, the structure of the unligated receptor reveals a homodimer assembly that might represent EphA2-specific homotypic cell adhesion interactions.</p>